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替尔泊肽减重后反弹的数据
停用替尔泊肽（Tirzepatide）后，绝大多数人会面临快速且大幅度的体重反弹，同时伴随此前因减重而改善的血压、血糖等健康指标再次恶化。现有的科学研究明确指出，一旦停止使用这种药物，患者在随后的一年内平均会反弹高达14%的体重，几乎抵消了绝大部分的减肥成果。
为了让您更全面、清晰地了解替尔泊肽停药后的真实数据与身体变化，我们将结合多项权威科学研究，用最通俗易懂的方式为您详细拆解。
一、 核心数据：停药后体重到底会反弹多少？
医学界对替尔泊肽的反弹情况进行了非常严谨的长期追踪。其中最具代表性的是一项名为“SURMOUNT-4”的大型国际临床研究。我们可以把这项研究看作是一个“分段式的减肥观察营”。
在这个观察营里，研究人员招募了670名伴有肥胖或超重问题（且不含糖尿病）的成年人。首先，所有人都在医生的指导下，连续打了36周（大约8个多月）的替尔泊肽。效果非常显著，大家的体重平均下降了20.9%。也就是说，一个200斤的人，大概能减掉40多斤。
但是，真正的考验在第36周之后开始。研究人员把这些人随机分成了两组：
- 继续用药组：一半的人继续打替尔泊肽，再打52周（大约1年）。
- 停药组（安慰剂组）：另一半的人被换成了“安慰剂”。这里需要解释一下安慰剂（Placebo）：这就是一种没有任何药物成分的“假药”（比如生理盐水），外观和真药一样，主要用来测试病人在没有真实药物作用下的自然反应。
一年后的结果令人吃惊：
- 停药组大幅反弹：那些换成安慰剂（即实际上停用了替尔泊肽）的人，在接下来的一年里，体重平均反弹了14.0%。这意味着他们辛辛苦苦减掉的肉，又长回来了一大半。
- 继续用药组持续变瘦：而那些继续坚持打替尔泊肽的人，体重不仅没有反弹，反而又平均下降了5.5%。
- 最终的减肥总成绩：从第一天算起直到第88周结束，一直用药的人总体重平均下降了25.3%；而中途停药的人，总体重只比最开始轻了9.9%。
另一项汇总了多项研究的“荟萃分析”（即把全世界相关的研究数据放在一起重新计算的大型研究）也得出了相同的结论。研究显示，停用类似替尔泊肽和司美格鲁肽这类的减重药物后，患者的体重会出现显著反弹，平均反弹重量达到了9.69公斤。并且，你一开始靠药物减掉的体重越多，停药后反弹的绝对重量往往也越大。此外，还有针对停药后患者的追踪研究发现，停药仅仅2个月、4个月、6个月后，体重就会出现与用药剂量相关的早期快速反弹。无论是用哪种剂量，停药后快速复胖是一个普遍规律。
二、 反弹的不仅仅是数字：对身体健康深层指标的影响
当我们谈论肥胖时，不能只盯着体重秤上的数字。体重的反弹，往往意味着身体内部环境的恶化。在上述的“SURMOUNT-4”研究中，科学家们不仅称了患者的体重，还深入测量了他们的“心脏代谢指标”。
什么是心脏代谢指标（Cardiometabolic parameters）？ 您可以把人体想象成一台精密的汽车。心脏代谢指标就像是汽车仪表盘上的各种警示灯，包括你的腰有多粗（腰围）、血管里的压力有多大（血压）、血液里的油脂多不多（血脂）、以及血液里的糖分高不高（血糖）。当这些指标不正常时，汽车（身体）就很容易出大故障（比如心脏病、中风）。
研究发现，停用替尔泊肽导致体重反弹后，这些重要的“仪表盘警示灯”再次亮起了红灯。具体来说，在停药的一年内，绝大多数人的体重反弹幅度超过了此前减掉体重的25%，这直接导致了以下健康指标的恶化：
- 腰围变粗：反弹最严重的人群（反弹了原来减掉体重的75%以上），腰围平均增加了14.7厘米。腰围变粗意味着内脏脂肪的重新堆积，这对心血管非常危险。
- 血压升高：伴随体重反弹，收缩压（也就是我们常说的高压）最高平均回升了10.4毫米汞柱。
- 胆固醇变差：血液中的“非高密度脂蛋白胆固醇”（可以简单理解为血液里的“坏胆固醇”，容易堵塞血管）也随之升高，反弹严重者升高了10.8%。
- 血糖控制变差：这里我们要引入一个词叫糖化血红蛋白（HbA1c）。它反映的是你过去两三个月内血液里糖分的平均水平。停药反弹后，患者的糖化血红蛋白平均上升了0.35%。在另一项针对2型糖尿病患者的观察研究中也证实，停用替尔泊肽后，糖化血红蛋白水平在短期内（两到六个月）就出现了重新升高的现象。
- 空腹胰岛素飙升：胰岛素是身体里用来降血糖的激素。反弹严重的人，空腹胰岛素水平大幅增加了26.3%甚至46.2%。这意味着身体对胰岛素变得不敏感了（即胰岛素抵抗加重），身体需要分泌更多的胰岛素才能勉强控制血糖，这是迈向糖尿病的危险信号。
相比之下，那些体重反弹很小（反弹幅度小于25%）的人，他们的腰围、坏胆固醇和胰岛素水平基本能维持在刚减完肥时的好状态。这就说明，停药后的健康恶化，主要就是由体重重新增长（反弹）带来的。
三、 为什么停药后会反弹？认识替尔泊肽的工作原理
很多人不明白，为什么我明明已经瘦下来了，胃也感觉变小了，一停药怎么又会吃胖呢？要搞懂这个问题，我们需要了解替尔泊肽是如何在人体内起作用的。
替尔泊肽是一种非常前沿的药物，在医学上被称为GIP和GLP-1受体双重激动剂。 这段专业术语听起来很吓人，但其实原理可以用生活中的例子来解释： 在我们吃饱饭后，我们的肠道会分泌一些天然的“信号兵”（也就是荷尔蒙，比如GIP和GLP-1）。这些信号兵有两个重要任务：第一，它们跑到胰腺那里，告诉身体“有糖分进来了，快分泌点胰岛素降糖”；第二，它们跑到大脑的指挥中心，大喊“肚子已经装满了，别再吃了！”，同时让胃里的食物排空得慢一点，让你长时间觉得很撑。
胖人的身体里，这些天然的信号兵往往不够用或者不够敏感。替尔泊肽就像是科学家在实验室里制造出来的“超级人造信号兵”。你打了一针替尔泊肽，身体里就充满了这些超级信号兵，你的大脑会一直觉得“我好饱”，你的胃也处于半休息状态，你自然就不想吃饭了。因为吃得少，身体只能去消耗储存的脂肪，于是你就瘦了。
那停药后发生了什么呢？ 当你停止注射替尔泊肽，体内的“超级信号兵”被慢慢代谢干净。你的大脑突然收不到“吃饱了”的信号了。更糟糕的是，人体经历了一次大幅度的体重下降后，身体的古老生存本能会被激活。大脑会认为你刚经历了一场饥荒，于是疯狂地发出“我饿了”的信号，同时降低身体的日常能量消耗，试图把你失去的脂肪拼命补回来。因为失去了药物的强制压制，哪怕你主观上想控制饮食，身体强烈的饥饿感和代谢改变也会让大多数人败下阵来，导致体重的快速反弹。
因此，替尔泊肽带来的减重效果并不是一劳永逸的。它的作用机制决定了它只是在“用药期间”替你踩住了食欲的刹车，一旦松开刹车（停药），车子就会因为惯性和重力再次滑下坡。
四、 科学的建议：我们该如何面对肥胖的治疗？
基于上述严谨的数据和人体复杂的生理机制，医学界得出了几个非常关键的结论，这也正是普通人必须建立的科学认知：
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要把肥胖当成“慢性病”来治，而不是“感冒”： 很多人觉得减肥药就像感冒药，病好了（瘦下来了）就可以停药。但科学研究告诉我们，肥胖其实更像高血压、糖尿病这样的慢性病。你吃降压药，血压正常了，一旦停药血压就会再次飙升。同理，使用替尔泊肽等药物治疗肥胖，它需要长期的、甚至可能是终身的干预来防止体重反弹和随之而来的健康风险。
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单纯靠个人毅力（生活方式干预）很难战胜停药后的反弹： 在SURMOUNT-4研究中，即使停药组的患者同样接受了健康饮食和运动的指导，但面对停药后汹涌而来的食欲和代谢改变，他们依然反弹了14%的体重。荟萃分析也指出，不管是否进行生活方式的干预，停用这类药物都会导致体重回升。这意味着反弹并不是因为患者“意志力薄弱”或“懒惰”，而是生理机制使然。
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未来的减重策略需要精细化管理： 如果因为各种原因（比如经济负担、副作用等）必须停用替尔泊肽，那么患者必须在医生的密切跟踪下进行。一些研究建议，未来的治疗思路可能不是突然彻底停药，而是寻找合适的最低维持剂量，或者摸索如何安全地减少剂量以防止反弹。对于确实需要减重的2型糖尿病患者，如果开具了替尔泊肽，强烈建议需要持续的处方支持，或者在停药时进行极其仔细的复查和随访，以防止血糖恶化和体重反弹。
总而言之，科学证据表明：替尔泊肽是一种非常强效的减重和降糖工具，但它的魔法必须在持续使用的情况下才能生效。一旦停药，身体原本的设定就会恢复，导致高达10公斤以上的大幅体重反弹，并且原本好转的腰围、血压、血糖等指标也会跟着再次变差。在决定使用这类药物之前，患者应与医生充分沟通，做好长期甚至终身管理的心理预期。
References
1Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.PubMed
Louis J Aronne, Naveed Sattar, Deborah B Horn, et al.
JAMA. 2024 Jan 2;331(1):38-48. doi: 10.1001/jama.2023.24945.
IMPORTANCE: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. OBJECTIVE: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. DESIGN, SETTING, AND PARTICIPANTS: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. INTERVENTIONS: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. MAIN OUTCOMES AND MEASURES: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. RESULTS: Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. CONCLUSIONS AND RELEVANCE: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04660643.
2Discontinuing glucagon-like peptide-1 receptor agonists and body habitus: A systematic review and meta-analysis.PubMed
Sara Berg, Hannah Stickle, Suzanne J Rose, et al.
Obes Rev. 2025 Aug;26(8):e13929. doi: 10.1111/obr.13929. Epub 2025 Apr 4.
Research on Glucagon-like peptide 1 receptor agonist (GLP-1RA) has mainly focused on the efficacy of weight loss and not the long-term efficacy of weight loss maintenance. This systematic review and meta-analysis aims to evaluate the sustainability of weight loss of patients taking GLP-1RAs following the discontinuation of the drug. EBSCOhost was used to simultaneously search Academic Search Premier, CINHAL Ultimate, Cochrane Central Register of Controlled Trials, MEDLINE with full text, Cochrane Database of Systematic Reviews, and separate PubMed search was systematically investigated using a predetermined search strategy from inception to February 1st, 2024. The authors extracted data regarding body weight change from baseline on treatment and off treatment, change in waist circumference from baseline on and off treatment, and change in BMI from baseline on and off treatment. Meta-analysis was conducted using RevMan (version 5.4) to calculate pooled mean differences using a Der Simonian-Laird Random Effects model. ResultsThe initial search yielded 497 relevant articles and, after screening, retained 8 randomized controlled trials comprised of 2372 participants, all with a BMI ≥ 27 kg/m. After discontinuing GLP-1RA therapy, weight regain was proportional to the original weight loss. Participants who took liraglutide regained 2.20 kg (95% CI 1.69 to 2.70, P < 0.00001), and participants taking semaglutide/tirzepatide regained 9.69 kg (95% CI 5.78 to 13.60, P < 0.00001). This systematic review and meta-analysis show that significant weight is regained after discontinuing GLP-1RA treatment, which should be discussed when stopping therapy. PRACTITIONER POINTS: Question: Does discontinuation of Glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment lead to significant weight gain? Findings: In this systematic review and meta-analysis, discontinuing GLP-1RA treatment led to a pooled overall mean weight regain of 2.20 kg in participants taking liraglutide and 9.69 kg in those patients prescribed semaglutide/tirzepatide. The proportion of weight regained was proportional to the amount originally lost. Meaning: Discontinuation of GLP-1RA treatment leads to weight regain, regardless of lifestyle interventions, and should therefore be considered a chronic therapy to prevent weight regain and associated undesirable outcomes related to obesity.
3Weight Regain After Liraglutide, Semaglutide or Tirzepatide Interruption: A Narrative Review of Randomized Studies.PubMed
Massimo Quarenghi, Silvia Capelli, Giulia Galligani, et al.
J Clin Med. 2025 May 28;14(11):3791. doi: 10.3390/jcm14113791.
The primary objective of this review is to analyze the effects on body weight of discontinuing therapy with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or tirzepatide in patients treated for obesity. In recent months, there has been a considerable increase in the utilization of GLP-1 RAs and GIP/GLP-1 RAs. However, the paucity of available data regarding their medium- to long-term safety remains a salient concern. Of particular significance is the observation of the weight curve following their suspension, a subject that has received scant attention to date. : For this, a bibliographic search was carried out in three electronic databases: PubMed, Cochrane Library and Google Scholar. The following filters were applied: A total of 427 references were identified, 178 articles were read in full, and 13 articles were included in the analysis. : The analysis showed a rapid regain of weight after cessation of therapy, regardless of the duration of the treatment with GLP-1 RA or GIP/GLP-1 RA. This rebound is likely to substantially mitigate the metabolic benefits attained through weight loss. Given the efficacy of these drugs, it is essential for future research to focus on elucidating the optimal duration of these treatments or identifying techniques or schemes that involve a reduction in dosages to prevent weight regain.
4Cardiometabolic Parameter Change by Weight Regain on Tirzepatide Withdrawal in Adults With Obesity: A Post Hoc Analysis of the SURMOUNT-4 Trial.PubMed
Deborah B Horn, Bruno Linetzky, Melanie J Davies, et al.
JAMA Intern Med. 2026 Feb 1;186(2):157-167. doi: 10.1001/jamainternmed.2025.6112.
IMPORTANCE: In the SURMOUNT-4 trial, most adults with obesity who had tirzepatide withdrawn following a 36-week treatment regained weight. The association between the degree of weight regain and cardiometabolic parameters after tirzepatide withdrawal is unknown. OBJECTIVE: To assess changes in cardiometabolic parameters by degree of weight regain after withdrawal of tirzepatide. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of the SURMOUNT-4 trial included tirzepatide-treated participants with 10% or greater weight reduction at week 36 initially randomized to placebo. Data were collected from March 2021 to May 2023, and data were analyzed from February 2024 to March 2025. INTERVENTIONS: After 36 weeks of tirzepatide treatment (maximum tolerated dose of 10 mg or 15 mg), participants were randomized 1:1 to continue tirzepatide or to switch to placebo for 52 weeks (week 36 to 88). MAIN OUTCOMES AND MEASURES: Changes from week 36 to week 88 in cardiometabolic parameters on tirzepatide withdrawal were assessed by the degree of weight regain at week 88 as a percentage of weight lost while receiving tirzepatide from week 0 to 36: less than 25%, 25% to less than 50%, 50% to less than 75%, and 75% or more. RESULTS: Of 308 included participants, 219 (71.1%) were female, 89 (28.9%) were male, and the mean (SD) age was 47.1 (12.2) years. There were 54 participants in the less than 25% weight regain group, 77 in the 25% to less than 50% group, 103 in the 50% to less than 75% group, and 74 in the 75% or more group. Baseline demographic and clinical characteristics were similar across categories. During the initial 36 weeks of tirzepatide treatment, participants' weight decreased and cardiometabolic parameters improved. After withdrawal of tirzepatide, from week 36 to week 88, the mean change in waist circumference increased by weight regain category (<25% weight regain, 0.8 cm; 95% CI, -1.0 to 2.6; 25% to <50%, 5.4 cm; 95% CI, 4.0-6.8; 50% to <75%, 10.1 cm; 95% CI, 8.9-11.3; ≥75%, 14.7 cm; 95% CI, 12.7-16.7; P < .001), as did systolic blood pressure (6.8 mm Hg [95% CI, 3.9-9.7], 7.3 mm Hg [95% CI, 4.8-9.8], 9.6 mm Hg [95% CI, 7.1-12.1], and 10.4 mm Hg [95% CI, 8.0-12.8], respectively; P = .002), non-high-density lipoprotein cholesterol (-0.4% [95% CI, -7.3 to 6.5], 1.6% [95% CI, -2.3 to 5.5], 8.4% [95% CI, 3.9-12.9], and 10.8% [95% CI, 5.3-16.3], respectively), hemoglobin A1c (0.14% [95% CI, 0.06-0.22], 0.15% [95% CI, 0.09-0.21], 0.27% [95% CI, 0.21-0.33], and 0.35% [95% CI, 0.29-0.41], respectively; P < .001), and fasting insulin (-4.0% [95% CI, -20.7 to 12.7], 15.4% [95% CI, 2.3-28.5], 46.2% [95% CI, 29.5-62.9], and 26.3% [95% CI, 9.6-43.0], respectively). Changes at week 88 in waist circumference, non-high-density lipoprotein cholesterol, and fasting insulin in those with less than 25% weight regain were not significantly different compared with week 36. CONCLUSIONS AND RELEVANCE: In this post hoc analysis of the SURMOUNT-4 trial, among participants with obesity who achieved weight reduction with 36-week tirzepatide treatment, withdrawing tirzepatide led to 25% or greater weight regain in most participants within 1 year and was associated with a greater reversal of their initial cardiometabolic parameter improvements compared with those who maintained weight reduction. These findings underscore the importance of continued obesity treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04660643.
5Effect on Hemoglobin A1c (HbA1c) and Body Weight After Discontinuation of Tirzepatide, a Novel Glucose-Dependent Insulinotropic Peptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist: A Single-Center Case Series Study.PubMed
Mitsunobu Kubota, Kazuki Yamamoto, Sayo Yoshiyama
Cureus. 2023 Oct 4;15(10):e46490. doi: 10.7759/cureus.46490. eCollection 2023 Oct.
Introduction The purpose of this study was to examine changes in blood glucose levels and body weight after discontinuation of tirzepatide, a novel long-acting dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA). Methods Nine subjects (five males, four females, age 54.3±5.4 years, body mass index 33.5±3.3 kg/m) participating with type 2 diabetes in the SURPASS J-mono study were included. Subjects were randomized to tirzepatide 5 mg, 10 mg, 15 mg, or a dulaglutide 0.75 mg group. Fifty-two weeks after randomization, study drug administration was discontinued. To investigate progress after the end of administration, changes in hemoglobin A1c (HbA1c) and body weight were further examined two, four, and six months after discontinuation of the study drug. Results After fifty-two weeks, all tirzepatide groups had improved HbA1c and body weight compared with the dulaglutide group. At two, four, and six months after the end of study drug administration, re-elevation of HbA1c was observed in all groups. Furthermore, in the tirzepatide groups, dose-dependent weight regain was observed from an early stage. Conclusions Compared to dulaglutide, tirzepatide exhibited excellent blood-glucose-improving and weight-reducing effects. However, exacerbation of blood glucose and rebound of weight gain occurred relatively early after administration was ended. For type 2 diabetes patients who need weight loss and are prescribed tirzepatide, these findings suggest a necessity for continuous prescription or careful follow-up when stopping.
6Tackling suboptimal clinical response after metabolic bariatric surgery: Impact of tirzepatide on weight loss and body composition.PubMed
Fabian Stoll, Tobias Kantowski, Jonas Laaser, et al.
Obes Res Clin Pract. 2025 Jan-Feb;19(1):63-69. doi: 10.1016/j.orcp.2025.02.004. Epub 2025 Feb 14.
INTRODUCTION: Insufficient weight loss (IWL) or weight regain (WR) after metabolic bariatric surgery remains a challenge in obesity management. Therefore, this study aimed to retrospectively evaluate the impact of adjunctive tirzepatide therapy over 6 months following sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). METHODS: Post-bariatric patients without type 2 diabetes with IWL or WR (n = 21) were analyzed. Key outcomes included changes in weight, BMI, waist circumference, body composition, basal metabolism, metabolic markers, and inflammatory markers. Subgroup analyses assessed differences based on sex, surgery type, and classification as IWL or WR. Linear regression was performed to identify predictors of weight loss outcomes. RESULTS: At 6 months, mean total weight loss was 12.0 % ± 3.4 % (p < 0.001), with significant reductions in BMI, waist circumference, body fat percentage, and HbA1c. Basal metabolism declined proportionally with weight loss. Weight loss ≥ 5 % occurred in 100.0 % of patients, ≥ 10 % in 76.5 %, and ≥ 15 % in 23.5 %. Basal metabolism differences between RYGB and SG patients converged by 6 months. Male and female patients showed comparable weight loss and metabolic adaptation. IWL patients experienced less fat-free mass loss at 3 months compared to WR (p < 0.05). Baseline BMI nadir, prior weight regain, body composition, and chronic inflammation were significant predictors of weight loss outcomes. DISCUSSION: Tirzepatide treatment significantly enhances weight loss and metabolic health in post-bariatric patients, regardless of surgery type or sex. Differences in fat-free mass loss highlight the need for tailored interventions in IWL and WR groups. Baseline factors, including inflammation and body composition, may help predict treatment success.
7Tirzepatide for Obesity Treatment and Diabetes Prevention.PubMed
Ania M Jastreboff, Carel W le Roux, Adam Stefanski, et al.
N Engl J Med. 2025 Mar 6;392(10):958-971. doi: 10.1056/NEJMoa2410819. Epub 2024 Nov 13.
BACKGROUND: Obesity is a chronic disease and causal precursor to myriad other conditions, including type 2 diabetes. In an earlier analysis of the SURMOUNT-1 trial, tirzepatide was shown to provide substantial and sustained reductions in body weight in persons with obesity over a 72-week period. Here, we report the 3-year safety outcomes with tirzepatide and its efficacy in reducing weight and delaying progression to type 2 diabetes in persons with both obesity and prediabetes. METHODS: We performed a phase 3, double-blind, randomized, controlled trial in which 2539 participants with obesity, of whom 1032 also had prediabetes, were assigned in a 1:1:1:1 ratio to receive tirzepatide at a once-weekly dose of 5 mg, 10 mg, or 15 mg or placebo. The current analysis involved the participants with both obesity and prediabetes, who received their assigned dose of tirzepatide or placebo for a total of 176 weeks, followed by a 17-week off-treatment period. The three key secondary end points, which were controlled for type I error, were the percent change in body weight from baseline to week 176 and onset of type 2 diabetes during the 176-week and 193-week periods. RESULTS: At 176 weeks, the mean percent change in body weight among the participants who received tirzepatide was -12.3% with the 5-mg dose, -18.7% with the 10-mg dose, and -19.7% with the 15-mg dose, as compared with -1.3% among those who received placebo (P<0.001 for all comparisons with placebo). Fewer participants received a diagnosis of type 2 diabetes in the tirzepatide groups than in the placebo group (1.3% vs. 13.3%; hazard ratio, 0.07; 95% confidence interval [CI], 0.0 to 0.1; P<0.001). After 17 weeks off treatment or placebo, 2.4% of the participants who received tirzepatide and 13.7% of those who received placebo had type 2 diabetes (hazard ratio, 0.12; 95% CI, 0.1 to 0.2; P<0.001). Other than coronavirus disease 2019, the most common adverse events were gastrointestinal, most of which were mild to moderate in severity and occurred primarily during the dose-escalation period in the first 20 weeks of the trial. No new safety signals were identified. CONCLUSIONS: Three years of treatment with tirzepatide in persons with obesity and prediabetes resulted in substantial and sustained weight reduction and a markedly lower risk of progression to type 2 diabetes than that with placebo. (Funded by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.).
8Subcutaneously administered tirzepatide vs semaglutide for adults with type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials.PubMed
Thomas Karagiannis, Konstantinos Malandris, Ioannis Avgerinos, et al.
Diabetologia. 2024 Jul;67(7):1206-1222. doi: 10.1007/s00125-024-06144-1. Epub 2024 Apr 13.
AIMS/HYPOTHESIS: We conducted a systematic review and network meta-analysis to compare the efficacy and safety of s.c. administered tirzepatide vs s.c. administered semaglutide for adults of both sexes with type 2 diabetes mellitus. METHODS: We searched PubMed and Cochrane up to 11 November 2023 for RCTs with an intervention duration of at least 12 weeks assessing s.c. tirzepatide at maintenance doses of 5 mg, 10 mg or 15 mg once weekly, or s.c. semaglutide at maintenance doses of 0.5 mg, 1.0 mg or 2.0 mg once weekly, in adults with type 2 diabetes, regardless of background glucose-lowering treatment. Eligible trials compared any of the specified doses of tirzepatide and semaglutide against each other, placebo or other glucose-lowering drugs. Primary outcomes were changes in HbA and body weight from baseline. Secondary outcomes were achievement of HbA target of ≤48 mmol/mol (≤6.5%) or <53 mmol/mol (<7.0%), body weight loss of at least 10%, and safety outcomes including gastrointestinal adverse events and severe hypoglycaemia. We used version 2 of the Cochrane risk-of-bias tool (ROB 2) to assess the risk of bias, conducted frequentist random-effects network meta-analyses and evaluated confidence in effect estimates utilising the Confidence In Network Meta-Analysis (CINeMA) framework. RESULTS: A total of 28 trials with 23,622 participants (44.2% female) were included. Compared with placebo, tirzepatide 15 mg was the most efficacious treatment in reducing HbA (mean difference -21.61 mmol/mol [-1.96%]) followed by tirzepatide 10 mg (-20.19 mmol/mol [-1.84%]), semaglutide 2.0 mg (-17.74 mmol/mol [-1.59%]), tirzepatide 5 mg (-17.60 mmol/mol [-1.60%]), semaglutide 1.0 mg (-15.25 mmol/mol [-1.39%]) and semaglutide 0.5 mg (-12.00 mmol/mol [-1.09%]). In between-drug comparisons, all tirzepatide doses were comparable with semaglutide 2.0 mg and superior to semaglutide 1.0 mg and 0.5 mg. Compared with placebo, tirzepatide was more efficacious than semaglutide for reducing body weight, with reductions ranging from 9.57 kg (tirzepatide 15 mg) to 5.27 kg (tirzepatide 5 mg). Semaglutide had a less pronounced effect, with reductions ranging from 4.97 kg (semaglutide 2.0 mg) to 2.52 kg (semaglutide 0.5 mg). In between-drug comparisons, tirzepatide 15 mg, 10 mg and 5 mg demonstrated greater efficacy than semaglutide 2.0 mg, 1.0 mg and 0.5 mg, respectively. Both drugs increased incidence of gastrointestinal adverse events compared with placebo, while neither tirzepatide nor semaglutide increased the risk of serious adverse events or severe hypoglycaemia. CONCLUSIONS/INTERPRETATION: Our data show that s.c. tirzepatide had a more pronounced effect on HbA and weight reduction compared with s.c. semaglutide in people with type 2 diabetes. Both drugs, particularly higher doses of tirzepatide, increased gastrointestinal adverse events. REGISTRATION: PROSPERO registration no. CRD42022382594.
9Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition?PubMed
João Carlos Locatelli, Juliene Gonçalves Costa, Andrew Haynes, et al.
Diabetes Care. 2024 Oct 1;47(10):1718-1730. doi: 10.2337/dci23-0100.
This narrative review highlights the degree to which new antiobesity medications based on gut-derived nutrient-stimulated hormones (incretins) cause loss of lean mass, and the importance of resistance exercise to preserve muscle. Glucagon-like peptide 1 receptor agonists (GLP-1RA) induce substantial weight loss in randomized trials, effects that may be enhanced in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. Liraglutide and semaglutide (GLP-1RA), tirzepatide (GLP-1 and GIP receptor dual agonist), and retatrutide (GLP-1, GIP, and glucagon receptor triple agonist) are peptides with incretin agonist activity that induce ∼15-24% weight loss in adults with overweight and obesity, alongside beneficial impacts on blood pressure, cholesterol, blood glucose, and insulin. However, these agents also cause rapid and significant loss of lean mass (∼10% or ∼6 kg), comparable to a decade or more of aging. Maintaining muscle mass and function as humans age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality. Studies indicate that supervised resistance exercise training interventions with a duration >10 weeks can elicit large increases in lean mass (∼3 kg) and strength (∼25%) in men and women. After a low-calorie diet, combining aerobic exercise with liraglutide improved weight loss maintenance compared with either alone. Retaining lean mass during incretin therapy could blunt body weight (and fat) regain on cessation of weight loss pharmacotherapy. We propose that tailored resistance exercise training be recommended as an adjunct to incretin therapy to optimize changes in body composition by preserving lean mass while achieving fat loss.
10Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity.PubMed
Patricia J Rodriguez, Brianna M Goodwin Cartwright, Samuel Gratzl, et al.
JAMA Intern Med. 2024 Sep 1;184(9):1056-1064. doi: 10.1001/jamainternmed.2024.2525.
IMPORTANCE: Although tirzepatide and semaglutide were shown to reduce weight in randomized clinical trials, data from head-to-head comparisons in populations with overweight or obesity are not yet available. OBJECTIVE: To compare on-treatment weight loss and rates of gastrointestinal adverse events (AEs) among adults with overweight or obesity receiving tirzepatide or semaglutide labeled for type 2 diabetes (T2D) in a clinical setting. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, adults with overweight or obesity receiving semaglutide or tirzepatide between May 2022 and September 2023 were identified using electronic health record (EHR) data linked to dispensing information from a collective of US health care systems. On-treatment weight outcomes through November 3, 2023, were assessed. Adults with overweight or obesity and regular care in the year before initiation, no prior glucagon-like peptide 1 receptor agonist receptor agonist use, a prescription within 60 days prior to initiation, and an available baseline weight were identified. The analysis was completed on April 3, 2024. EXPOSURES: Tirzepatide or semaglutide in formulations labeled for T2D, on or off label. MAIN OUTCOMES AND MEASURES: On-treatment weight change in a propensity score-matched population, assessed as hazard of achieving 5% or greater, 10% or greater, and 15% or greater weight loss, and percentage change in weight at 3, 6, and 12 months. Hazards of gastrointestinal AEs were compared. RESULTS: Among 41 222 adults meeting the study criteria (semaglutide, 32 029; tirzepatide, 9193), 18 386 remained after propensity score matching. The mean (SD) age was 52.0 (12.9) years, 12 970 were female (70.5%), 14 182 were white (77.1%), 2171 Black (11.8%), 354 Asian (1.9%), 1679 were of other or unknown race, and 9563 (52.0%) had T2D. The mean (SD) baseline weight was 110 (25.8) kg. Follow-up was ended by discontinuation for 5140 patients (55.9%) receiving tirzepatide and 4823 (52.5%) receiving semaglutide. Patients receiving tirzepatide were significantly more likely to achieve weight loss (≥5%; hazard ratio [HR], 1.76, 95% CI, 1.68, 1.84; ≥10%; HR, 2.54; 95% CI, 2.37, 2.73; and ≥15%; HR, 3.24; 95% CI, 2.91, 3.61). On-treatment changes in weight were larger for patients receiving tirzepatide at 3 months (difference, -2.4%; 95% CI -2.5% to -2.2%), 6 months (difference, -4.3%; 95% CI, -4.7% to -4.0%), and 12 months (difference, -6.9%; 95% CI, -7.9% to -5.8%). Rates of gastrointestinal AEs were similar between groups. CONCLUSIONS AND RELEVANCE: In this population of adults with overweight or obesity, use of tirzepatide was associated with significantly greater weight loss than semaglutide. Future study is needed to understand differences in other important outcomes.
11Weight Loss Blockbuster Development: A Role for Unimolecular Polypharmacology.PubMed
Qingtong Zhou, Guanyi Li, Kaini Hang, et al.
Annu Rev Pharmacol Toxicol. 2025 Jan;65(1):191-213. doi: 10.1146/annurev-pharmtox-061324-011832. Epub 2024 Dec 17.
Obesity and type 2 diabetes mellitus (T2DM) impact more than 2.5 billion adults worldwide, necessitating innovative therapeutic approaches. Unimolecular polypharmacology, which involves designing single molecules to target multiple receptors or pathways simultaneously, has revolutionized treatment strategies. Blockbuster drugs such as tirzepatide and retatrutide have shown unprecedented success in managing obesity and T2DM, demonstrating superior efficacy compared to conventional single agonists. Tirzepatide, in particular, has garnered tremendous attention for its remarkable effectiveness in promoting weight loss and improving glycemic control, while offering additional cardiovascular and renal benefits. Despite their promises, such therapeutic agents also face challenges that include gastrointestinal side effects, patient compliance issues, and body weight rebound after cessation of the treatment. Nonetheless, the development of these therapies marks a significant leap forward, underscoring the transformative potential of unimolecular polypharmacology in addressing metabolic diseases and paving the way for future innovations in personalized medicine.
12Semaglutide and Tirzepatide for the Management of Weight Recurrence After Sleeve Gastrectomy: A Retrospective Cohort Study.PubMed
Mohammad Jamal, Mohsen Alhashemi, Carol Dsouza, et al.
Obes Surg. 2024 Apr;34(4):1324-1332. doi: 10.1007/s11695-024-07137-0. Epub 2024 Mar 2.
BACKGROUND: Metabolic and bariatric surgery (MBS) is the most effective treatment for obesity and improvement of obesity-associated comorbidities. However, a proportion of these patients may suffer from weight recurrence and recurrence of obesity-associated comorbidities. METHOD: A retrospective cohort study of patients who underwent SG between January 2008 and August 2022 and sought treatment for weight recurrence with semaglutide or tirzepetide from January 2022 onwards. RESULT: A total of 115 patients were included, of which 70 had SG and treated for weight recurrence with semaglutide and 45 had SG and treated with tirzepatide. The mean age of patients was 38.8 (10.4) and 80.9% of patients were female. The mean pre-treatment weight and BMI was 94.0 (23.8) kg and 35.1 (6.0) kg/m. Following treatment with semaglutide and tirzepatide, the mean post-treatment weight at 6 months was 81.0 (19.0) kg from 90.1 (19.6) kg and 87.6 (28.3) kg from 100.2 (28.5) kg respectively, corresponding to a clinically significant mean weight loss from baseline to 6 months of 10.3 (5.9)% (p < 0.05) and 15.5 (6.3)% (p < 0.05). Weight loss in tirzepatide patients was significantly greater than the semaglutide patients at 6 months (p < 0.02). There were no reported severe adverse events to the treatment. CONCLUSION: Short-term outcomes show that semaglutide and tirzepatide can be an effective treatment for managing weight recurrence after SG. Studies with longer follow-up are needed to determine the durability, as weight regain after discontinuation of the medication is highly likely, and the high cost of these medications can limit their use.
13Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now?PubMed
Prathima Gogineni, Eka Melson, Dimitris Papamargaritis, et al.
Expert Opin Pharmacother. 2024 May;25(7):801-818. doi: 10.1080/14656566.2024.2356254. Epub 2024 May 22.
INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of type 2 diabetes (T2D) management due to their cardio-renal benefits, their glucose-lowering efficacy and weight loss (WL) maintenance. However, the response to GLP-1 RA monotherapy is heterogeneous. Additionally, the majority of GLP-1 RAs are injectable treatments. Oral GLP-1 RAs and injectable combinations of GLP-1 with other entero-pancreatic hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin) are under development for T2D and obesity management. AREAS COVERED: Herein, we review the data on (i) oral GLP-1 RAs (oral semaglutide 25/50 mg and orforglipron) and (ii) dual/triple agonists (tirzepatide, cagrilintide 2.4 mg/semaglutide 2.4 mg, survodutide, mazdutide, retatrutide) that have recently completed phase 3 trials for T2D or are currently in phase 3 clinical trials. Tirzepatide is the first approved dual agonist (GLP-1/GIP) for T2D and obesity management. EXPERT OPINION: We are in a new era in T2D management where entero-pancreatic hormone-based treatments can result in ≥15% WL and euglycemia for many people with T2D. Multiple molecules with different mechanisms of action are under development for T2D, obesity and other metabolic complications. Data on their cardio-renal benefits, long-term efficacy and safety as well as their cost-effectiveness will better inform their position in treatment algorithms.
14Comparative analysis of LJ-4378 and tirzepatide in mouse models of obesity and weight regain.PubMed
Heeseong Kim, Seung Woo Kim, Cheoljun Choi, et al.
Arch Pharm Res. 2025 Dec;48(11-12):1441-1459. doi: 10.1007/s12272-025-01575-9. Epub 2025 Nov 7.
We previously developed LJ-4378, a dual ligand for A and A adenosine receptors, as a potential anti-obesity agent. In this study, we compared the anti-obesity effects of LJ-4378 with those of tirzepatide (TZP), a dual agonist of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, and one of the most potent FDA-approved obesity therapeutics. Using a mouse model of diet-induced obesity, we assessed the effects of LJ-4378 and TZP on body weight loss, metabolic parameters, and post-treatment weight rebound. Mice fed a high-fat diet (HFD) for 10 weeks were treated with vehicle, LJ-4378, or TZP for 14 days. Both LJ-4378 and TZP significantly reduced body weight, adipose tissue mass, and abdominal fat volume; improved glucose tolerance; reduced white adipose tissue inflammation; and enhanced energy expenditure. To assess the durability of the treatment effects, drug administration was discontinued after 14 days, and the mice remained on the HFD for an additional 4 weeks. Notably, LJ-4378-treated mice exhibited attenuated body weight regain, stable food intake, persistent metabolic benefits, and sustained enhancement of energy metabolism, compared to TZP-treated mice. These findings highlight LJ-4378 as an anti-obesity agent that functions independently of appetite suppression and may offer superior long-term benefits by limiting post-treatment weight rebound and preserving metabolic improvements.
15Psychotropic Drug-Related Weight Gain and Its Treatment.PubMed
Roger S McIntyre, Angela T H Kwan, Joshua D Rosenblat, et al.
Am J Psychiatry. 2024 Jan 1;181(1):26-38. doi: 10.1176/appi.ajp.20230922.
Psychotropic drug-related weight gain (PDWG) is a common occurrence and is highly associated with non-initiation, discontinuation, and dissatisfaction with psychiatric drugs. Moreover, PDWG intersects with the elevated risk for obesity and associated morbidity that has been amply reported in the psychiatric population. Evidence indicates that differential liability for PDWG exists for antipsychotics, antidepressants, and anticonvulsants. During the past two decades, agents within these classes have become available with significantly lower or no liability for PDWG and as such should be prioritized. Although lithium is associated with weight gain, the overall extent of weight gain is significantly lower than previously estimated. The benefit of lifestyle and behavioral modification for obesity and/or PDWG in psychiatric populations is established, with effectiveness similar to that in the general population. Metformin is the most studied pharmacological treatment in the prevention and treatment of PDWG, and promising data are emerging for glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., liraglutide, exenatide, semaglutide). Most pharmacologic antidotes for PDWG are supported with low-confidence data (e.g., topiramate, histamine-2 receptor antagonists). Future vistas for pharmacologic treatment for PDWG include large, adequately controlled studies with GLP-1 receptor agonists and possibly GLP-1/glucose-dependent insulinotropic polypeptide co-agonists (e.g., tirzepatide) as well as specific dietary modifications.
16Tirzepatide Once Weekly for the Treatment of Obesity.PubMed
Ania M Jastreboff, Louis J Aronne, Nadia N Ahmad, et al.
N Engl J Med. 2022 Jul 21;387(3):205-216. doi: 10.1056/NEJMoa2206038. Epub 2022 Jun 4.
BACKGROUND: Obesity is a chronic disease that results in substantial global morbidity and mortality. The efficacy and safety of tirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in people with obesity are not known. METHODS: In this phase 3 double-blind, randomized, controlled trial, we assigned 2539 adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period. Coprimary end points were the percentage change in weight from baseline and a weight reduction of 5% or more. The treatment-regimen estimand assessed effects regardless of treatment discontinuation in the intention-to-treat population. RESULTS: At baseline, the mean body weight was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher. The mean percentage change in weight at week 72 was -15.0% (95% confidence interval [CI], -15.9 to -14.2) with 5-mg weekly doses of tirzepatide, -19.5% (95% CI, -20.4 to -18.5) with 10-mg doses, and -20.9% (95% CI, -21.8 to -19.9) with 15-mg doses and -3.1% (95% CI, -4.3 to -1.9) with placebo (P<0.001 for all comparisons with placebo). The percentage of participants who had weight reduction of 5% or more was 85% (95% CI, 82 to 89), 89% (95% CI, 86 to 92), and 91% (95% CI, 88 to 94) with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35% (95% CI, 30 to 39) with placebo; 50% (95% CI, 46 to 54) and 57% (95% CI, 53 to 61) of participants in the 10-mg and 15-mg groups had a reduction in body weight of 20% or more, as compared with 3% (95% CI, 1 to 5) in the placebo group (P<0.001 for all comparisons with placebo). Improvements in all prespecified cardiometabolic measures were observed with tirzepatide. The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively. CONCLUSIONS: In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight. (Supported by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.).
17Model-based simulation of glycaemic effect and body weight loss when switching from semaglutide or dulaglutide to once weekly tirzepatide.PubMed
Shweta Urva, Joshua A Levine, Karen Schneck, et al.
Curr Med Res Opin. 2024 Apr;40(4):567-574. doi: 10.1080/03007995.2024.2322072. Epub 2024 Mar 12.
OBJECTIVE: To evaluate the efficacy endpoints of HbA1c and body weight loss after switching from the GLP-1 receptor agonists, semaglutide or dulaglutide, to treatment with the GIP/GLP-1 receptor agonist (RA) tirzepatide. METHODS: Models were developed and validated to describe the HbA1c and weight loss time course for semaglutide (SUSTAIN 1-10), dulaglutide (AWARD-11) and tirzepatide (SURPASS 1-5, phase 3 global T2D program). The impact of switching from once weekly GLP-1 RAs to tirzepatide was described by simulating the efficacy time course. Semaglutide and dulaglutide doses were escalated in accordance with their respective labels. RESULTS: Model-predicted mean decreases from baseline in HbA1c and body weight for semaglutide 0.5 mg, 1 mg, and 2 mg were 1.22 to 1.79% and 3.62 to 6.87 kg respectively, at Week 26. Model-predicted mean decreases from baseline in HbA1c and body weight for dulaglutide 1.5 mg, 3 mg and 4.5 mg were 1.53 to 1.84% and 2.55 to 3.71 kg respectively, at Week 26. After switching to tirzepatide 5, 10 and 15 mg HbA1c reductions were predicted to range between 1.95 to 2.46% and body weight reductions between 6.50 to 12.1 kg by Week 66. CONCLUSION: In this model-based simulation, switching from approved maintenance doses of semaglutide or dulaglutide to tirzepatide, even at the lowest approved maintenance dose of 5 mg, showed the potential to further improve HbA1c and body weight reductions.
18Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.PubMed
Haiqiang Yao, Anqi Zhang, Delong Li, et al.
BMJ. 2024 Jan 29;384:e076410. doi: 10.1136/bmj-2023-076410.
OBJECTIVE: To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible. RESULTS: 76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration. CONCLUSIONS: GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022342845.
19Sleeve-to-bypass conversion vs. sleeve-with-adjuvant GLP-1 receptor agonists: an academic multicenter retrospective study.PubMed
Avery Brown, Helena Sergent, Alexander Hien Vu, et al.
Surg Endosc. 2025 Sep;39(9):6155-6162. doi: 10.1007/s00464-025-11942-8. Epub 2025 Jul 21.
INTRODUCTION: GLP-1 receptor agonists (GLP1-RAs) are increasingly prescribed as an alternative to bariatric surgery for weight loss, and may pose as an alternative to conversion Roux-En-Y Gastric Bypass (cRYGB) in patients with insufficient weight loss or weight recurrence after sleeve gastrectomy [A C, N C, A I. Postoperative morbidity and weight loss after revisional bariatric surgery for primary failed restrictive procedure: a systematic review and network meta-analysis. International Journal of Surgery; 2022;Jensen et al. in Obes Surg 33:1017-1025, 2023; Jamal et al. in Obes Surg 34:1324-1332, 2024; Lautenbach A, Wernecke M, Stoll FD, Meyhöfer SM, Meyhöfer S, Aberel J. 1422-P: The potential of semaglutide once-weekly in patients without Type 2 Diabetes with weight regain or insufficient weight loss after bariatric surgery. Diabetes 2022; 71(Supplement_1);]. METHODS AND PROCEDURES: Adult patients ≥ 18 years old, who previously underwent a sleeve gastrectomy and were subsequently treated with weekly injectable Semaglutide or Tirzepatide, or treated with conversion from sleeve gastrectomy were included for analysis. Patients converted for GERD, GLP1-RA use with BMI ≤ 35, or pre operative GLP1-RA use were excluded. Post operative weights and Hgb A1C were assessed from 3 months to 3 years post intervention (start of GLP1-RA or surgery). T-test, ANOVA, and chi-squared analysis were used to compare groups, while multivariable linear regression analysis was used to evaluate the effect of bariatric surgery on %TBWL at 3 years post intervention when adjusting for baseline characteristics. RESULTS: 4901 patients were included for analysis (3004 cRYGB, 1897 GLP1-RA). There was no difference in pre-intervention weight (242.8 ± 44.4 GLP1-RA vs 242.3 ± 57.8 cRYGB, p = .993). cRYGB patients had a higher baseline Hgba1c (6.19 ± 1.4 vs 5.85 ± 1.2, p < 0.001). cRYGB was associated with significantly greater weight loss at all post operative time points up to 3 years post intervention, (26.1 vs 13.7%, p < 0.001). There was no significant difference in Hgba1c control between treatments at all post intervention time points (all p > 0.05). In the multivariate linear regression analysis, when adjusting for sex, baseline BMI, baseline age, and non-white race, cRYGB was associated with an 11% greater %TBWL compared to those who were treated with a GLP1-RA. CONCLUSIONS: For patients who have had insufficient weight loss or weight recurrence following sleeve gastrectomy, conversion to RYGB offers greater, long-term weight loss compared to GLP1-RAs.